Il ruolo della
farmacologia clinica nella personalizzazione
delle terapie oncologiche
Marzia Del Re
Biochimica clinica
UOC Farmacologia clinica e Farmacogenetica
AOUP
What a pharmacologist can do with a blood sample?
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PROVETTA DI SANGUE Accedi
2
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PROVETTA DI SANGUE Accedi
-analysis of germinal DNA to predict drug toxicity
3
What a pharmacologist can do with a
blood sample?
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PROVETTA DI SANGUE Accedi
-analysis of germinal DNA to predict drug toxicity
-therapeutic drug monitoring
4
What a pharmacologist can do with a
blood sample?
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PROVETTA DI SANGUE Accedi
-analysis of germinal DNA to predict drug toxicity
-therapeutic drug monitoring -tumor response/acquired resistance monitoring
5
What a pharmacologist can do with a
blood sample?
PREDICTIVE BIOMARKERS
Drug activity Drug toxicity
What a pharmacologist can do with a
blood sample?
7
PREDICTIVE BIOMARKERS
Drug activity Drug toxicity
What a pharmacologist can do with a
blood sample?
8
Toxicity biomarkers currently used in cancer care
Gruppo di lavoro AI O M -SIF
RACCO M AN D AZIO N I PER AN ALISI FARM ACO GEN ETICH E D PD E FLUO RO PIRIM ID IN E
1. Indicazioni cliniche
Le fluoropirimidine possono provocare tossicità gastrointestinale ed ematologica anche gravi riconducibili a deficit del loro metabolismo inattivante dipendente dalla diidropirimidina deidrogenasi (DPD), enzima chiave di tale processo. Il gene codificante per l’enzima DPD, DPYD, può infatti presentare alterazioni (polimorfismi) risultanti in una ridotta attività enzimatica.
L'analisi farmacogenetica di DPYD è raccomandabile:
1.a In pre-terapia con fluoropirimidine (5-FU, capecitabina, tegafur) ogni qual volta, a giudizio dell’oncologo, il trattamento venga proposto per un paziente in cui, per le caratteristiche cliniche (comorbilità , PS, stadio di malattia) il vantaggio terapeutico in termini di sopravvivenza e/ o risposta possa ipotizzarsi di limitato impatto e / o sia elevato il rapporto rischio/ beneficio.
1.b In post -terapia con fluoropirimidine (5-FU, capecitabina, tegafur) nei casi di tossicità gastrointestinale di grado ≥ 3 e/o ematologica di grado 4 (NCI-CTCAE v.4.0), verificatisi dopo l’inizio della terapia e in tutti i casi di tossicità inattese.
2. M at eriale biologico e document azione necessaria per l’analisi molecolare
L’analisi molecolare del gene DPYD viene effettuata su DNA germinale estratto da sangue periferico. Il sangue va raccolto in provetta con anticoagulante (EDTA) e sono necessari almeno 2 ml di sangue. Il sangue può essere conservato in attesa di processamento a breve termine in provetta chiusa sterile preferibilmente a temperatura di +4 °C per un periodo massimo di 5 giorni o anche a temperatura ambiente per un periodo massimo di 48 ore o, in caso di processamento a medio termine, congelato a -20°C.
Il campione deve essere accompagnato da:
2.a richiesta su ricetta del SSN o opportuna documentazione ospedaliera per i pazienti ricoverati nei DH delle strutture richiedenti con la seguente dicitura
“ analisi molecolare DPYD pre-t rat t ament o ” oppure “ analisi molecolare DPYD post -t rat t ament o ” ;
2.b scheda riassuntiva del regime chemioterapico con fluoropirimidine e dei
trattamenti concomitanti (per valutare interazioni a carico dell’enzima DPD). In
DPD deficiency and 5-FU toxicity
9 61C>T
62G>A 74A>G 85T>C
257C>T 295-298delTCAT
100delA
496A>G 601A>C 632A>G
703C>T 812delT
Introne
5’
Esone
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
3’
1003G>T 1039delTG
1108A>G
1156G>T 1475 C>T
1601G>A 1627A>G 1679T>G 1714C>G
1896T>C 1897delC IVS14+1G>A
2194G>A
2657G>A 2846A>T
2933A>G 2983G>T
Del Re M et al. EPMA Journal 2011
J Natl Cancer Inst. 2014 Nov 7;106(12)
“…In light of the current results, clinicians are strongly encour- aged to consider testing for *2A and D949V in patients treated with either 5-FU– or capecitabine-based regimens.
Understanding the implications of DPYD deficiency will lead to
a more precise management of cancer patients treated with
these agents.”
Henricks LM, Lunenburg CA, Meulendijks D, Gelderblom H, Cats A, Swen JJ, Schellens JH, Guchelaar HJ.
Pharmacogenomics. 2015 Jul;16(11):1-10
11
DHU/U ratio according to DPYD genotype
Pharmacogenomics. 2015 Jul;16(11):1-10
Gene activity score
Pharmacogenomics. 2015 Jul;16(11):1-10
13DOI: http://dx.doi.org/10.1016/S1470-2045(15)00286-
14The italian DPD story…
200 5-FU patients suffering from GI and not GI severe toxicity
Sequencing of the entire DPYD gene Identification of 8 5-FU-toxicity associated SNPs
Validation of the 8 DPD SNPs
1000 patients suffering from GI and not GI severe toxicity
200 5-FU treated patients with good treatment tolerance
3 out of 8 SNPs were present in control population in hetero and homozogous conditions
4 deaths after 5-FU
adminstration. Patients were carriers of DPYD*2A or c.2846T
alleles
15AIOM-SIF Clinical recommendations
“La terapia con fluoropirimidine è controindicata nei pazienti
con gene DPYD mutato in omozigosi per le varianti DPYD*2A,
c.1679T>G e c.2846A>T, poiché esse annullano l’attività
enzimatica DPD, mentre è necessario ridurre il dosaggio della
fluoropirimidina almeno del 50% nei pazienti portatori delle
mutazioni DPYD*2A, c.1679T>G e c.2846A>T in eterozigosi. La
modifica della dose dovrà, inoltre, considerare anche eventuali
trattamenti concomitanti.”
17
PREDICTIVE BIOMARKERS
Drug activity Drug toxicity
What a pharmacologist can do with a
blood sample?
Treatment-dependent clonal selection
Multiple mechanisms of cftDNA release
J Clin Oncol. 2014 Feb;32(6):579-86
Applications of cftDNA
• Assessment of molecular tumor heterogeneity
• Monitoring of tumor dynamics related to treatment
• Identification of genetic determinants for targeted therapy
• Evaluation of early treatment response
• Assessment of evolution of resistance in real time
What to look for..?
• Acquired resistance to TKIs in NSCLC (p.T790M EGFR;
ALK translocation and point mutations)
Mechanisms of EGFR-TKIs acquired
resistance
0 10 20 30 40 50 60
Basal PD on gefitinib
Response to AZD9291
PD on AZD9291
% of E G FR mu ta tion s (c on c/ ul )
EGFR plasma mutations follw-up
p.L858R
PD on gefitinib
#REF!
p.L858R p.T790M
Acquired resistance monitoring in NSCLC
Mutant allele amplification
Wild type allele amplification
Sample ID 36 - EGFR p.T790M at gefitinib
progression
Mutant allele amplification
Wild type allele amplification
Sample ID 36 - EGFR p.T790M in response to
AZD9291
What to look for..?
• Acquired resistance to TKIs in NSCLC (p.T790M EGFR;
ALK translocation and point mutations)
• Acquired resistance to antiEGFR in colon cancer (RAS
mutations)
0 10 20 30 40 50 60
Baseline 1 PD CT scan + FU
P e rce n tag e of mu tan t alle le (%) 2 PD KRAS p.G12D
Oct.
2013
Jul.
2014
Oct.
2014
Jan.
2015 FOLFOXIRI
+CET
FOLFOX+BE V
FOLFOX+BE V
TAS-102
Clonal evolution and resistance to antiEGFR
treatment
What to look for..?
• Acquired resistance to TKIs in NSCLC (p.T790M EGFR;
ALK translocation and point mutations)
• Acquired resistance to antiEGFR in colon cancer (RAS mutations)
• Acquired resistance to hormonal treatment in breast
cancer (ER mutations)
NATURE REVIEWS|CLINICAL ONCOLOGY VOLUME 10 | JULY 2013 | 377 Vall d’Hebron Institute of Oncology,
Vall d’Hebron University Hospital, Paseo Vall d’Hebron 119–129, 08035 Barcelona, Spain
(L. De Mattos-Arruda, J. Cortes, A. Vivancos, J. Tabernero, J. Seoane), Translational Research Unit, Department of Medical Oncology
“ Sandro Pitigliani” , Istituto Toscano Tumori, Piazza Ospedale 5, 59100 Prato, Italy (L. Santarpia).
Department of Pathology and Human Oncology and Pathogenesis Program, Memorial
Sloan–Kettering Cancer Center,
1275 York Avenue, New York, NY 10065, USA (J. S. Reis-Filho).
Correspondence to:
L. De Mattos-Arruda ldmattos@
ir.vhebron.net
Circulating tumour cells and cell-free DNA as tools for managing breast cancer
Leticia De Mattos-Arruda, Javier Cortes, Libero Santarpia, Ana Vivancos, Josep Tabernero, Jorge S. Reis-Filho and Joan Seoane
Abstract | Circulating blood biomarkers promise to become non-invasive real-time surrogates for tumour tissue- based biomarkers. Circulating biomarkers have been investigated as tools for breast cancer diagnosis, the dissection of breast cancer biology and its genetic and clinical heterogeneity, prognostication, prediction and monitoring of therapeutic response and resistance. Circulating tumour cells and cell-free plasma DNA have been analysed in retrospective studies, and the assessment of these biomarkers is being incorporated into clinical trials. As the scope of breast cancer intratumour genetic heterogeneity unravels, the development of robust and standardized methods for the assessment of circulating biomarkers will be essential for the realization of the potentials of personalized medicine. In this Review, we discuss the current status of blood- born biomarkers as surrogates for tissue-based biomarkers, and their burgeoning impact on the management of patients with breast cancer.
De Mattos-Arruda, L. et al. Nat. Rev. Clin. Oncol. 10, 377–389 (2013); published online 28 May 2013; doi:10.103 8/ nrclinonc.2013.80
Int roduct ion
Circulating blood biomarkers promise to constitute non-invasive real-time surrogates for diagnosis, prog- nosis, therapeutic response or resistance monitoring, and as tools for assessing intratumour hetero geneity.1,2 Breast cancer is now perceived to be a collection of hetero geneous diseases, each with its own genetic profile, clinical behaviour, response to therapy and outcome.3 Microarray-based gene-expression profiling has changed our understanding of breast cancer biology.
There are several lines of evidence demonstrating that oestrogen receptor (ER)-positive and ER-negative breast cancers constitute fundamentally different dis- eases at the transcrip tomic and genetic levels,4,5 and that both ER-positive and ER-negative breast cancers can be subclassified into molecular subtypes.6 Not only are the ‘intrinsic subtypes’—luminal A, luminal B, HER2- enriched and basal-like breast cancer—being incorpor- ated into the design of clinical trials, but also additional molecular subtypes are still being discovered.7,8 However, for clinical decision making breast cancers are still classi- fied on the basis of histological grade, histological type, and ER, progesterone receptor (PR) and HER2 status.4 The selection of breast cancer treatment is based on these biomarkers, and complemented by ancillary methods that include proliferation surrogates, namely first- generation prognostic signatures (such as Oncotype Dx®, Genomic Health Redwood City, CA; and MammaPrint®, Agendia, Amsterdam, The Netherlands) and Ki-67.9
The characterization of the molecular profiles of the different breast cancer subtypes and the signalling
pathways they are addicted to is germane to the trans- lation of molecular biology and genomics into benefits for patients with breast cancer. However, recent studies have demonstrated the existence of spatial and temporal intratumour genetic heterogeneity within cancers.10–13 It is now accepted that the repertoire of mutations found within a given tumour might differ according to the region sampled, between primary tumour and metastatic deposits, and even between distinct metastatic depos- its.12 Therefore, it remains to be determined whether the optimal assessment of the repertoire of molecu- lar alterations in cancer cells should be performed on primar y tumour tissue, metastatic deposits, and/or circulating biomarkers.
There is a burgeoning interest in circulating bio- markers, given their potential in the translational arena and because they might constitute representative read- outs of both primary tumour and metastatic deposits, and provide ways to expedite the discovery and valida- tion of clinically useful predictive biomarkers. In the clinical management of patients with breast cancer, cir- culating biomarkers are of great interest in various con- texts: first, when primary tumour or metastatic tissue samples are not available; second, as a means to provide a longitudinal analysis of the molecular characteristics of cancer cells; third, as tools for monitoring response to systemic therapies in the neoadjuvant, adjuvant and meta static settings, and to assess minimal residual disease in the non- metastatic setting; fourth, as possible diagnostic surrogates; and, finally, as a means to address the challenges posed by intratumour genetic hetero- geneity. We review the current status of blood-born bio- markers as surrogates for tissue-based biomarkers, and
Competing interests
The authors declare no competing interests.
REVIEWS
© 2013 Macmillan Publishers Limited. All rights reserved
NATURE REVIEWS
|
CLINICAL ONCOLOGY VOLUME 10|
JULY 2013|
385a marker of a population enriched for CSCs.
117Likewise, NOTCH1, which is a breast cancer oncogene related to self-renewing of breast cancer initiating cells, is reported to be expressed in approximately 60% of CTCs.
118CTCs i n the bloodstream are consi dered to be enriched in CSCs,
119and this could further drive tumour initiation and, therefore, metastasis. Although there are many questions yet to be answered in this field, the detec- tion and molecular characterization of circulating CSCs could potentially have an impact on our understanding of metastasis in breast cancer, mechanisms of resistance and how circulating biomarkers should be assessed. An alternative interpretation for the observations that CTCs have phenotypic characteristics consistent with those of CSCs is that CTCs might be the result of an epithelial- to-mesenchymal (EMT) transition, and that numerous
markers and transcription factors expressed in cells undergoing EMT are also expressed in cells with CSC properties.
120Notably, EMT has been reported in CTCs obtained from patients with breast cancer.
121A dynamic balance of CTCs to either epithelial or mesenchymal states has been reported, and a mesenchymal CTC state has been shown to be associated with disease progression and therapeutic failure.
121It should be noted that mesen- chymal CTCs expressed EMT regulators, including compo nents of the TGF-β signalling pathway. Further studies to define whether CTCs are enriched for CSCs or cells undergoing EMT are warranted.
Clinically useful tools
Despite the interest in the implementation of circulat- ing biomarkers for the assessment of breast cancers, the
Figure 2 | Hypothesis for intratumour heterogeneity, therapeutic resistance and the potential role of blood-born circulating biomarkers. The model illustrates breast cancers harbouring intratumour heterogeneity, and how circulating biomarkers—
CTCs and ctDNA—constitute valuable non-invasive tools to recapitulate intratumour genomic characteristics. Graphs on the right show frequency of genomic alteration over time (for example, ctDNA copies/ ml or DNA extracted from CTCs).
a | There is a lack of tumour tissue after adjuvant therapy or during metastatic PD. MPS of circulating biomarkers could reveal molecular targets and a therapy X might be offered. b | MPS of both archival tumour tissue and circulating biomarkers reveal genomic alterations during PD, and one genomic alteration dominates in blood. Therapy X might be offered and there is reduction of one alteration (effective therapeutic intervention) while the other rises, indicating therapeutic resistance.
c | MPS of two metastatic sites, or the primary tumour and a metastatic deposit during PD give discordant results.
d | Spatial genetic heterogeneity within the primary tumour and/ or a metastatic deposit means that not all clones are sampled with a single biopsy. In parts c and d: MPS of circulating biomarkers could assist in the timely finding of actionable genomic alterations and in the clinical decision-making process. Abbreviations: CTCs, circulating tumour cells; ctDNA, cell-free tumour DNA; M, metastatic deposit; MPS, massively parallel sequencing; PD, progressive disease.
50
0 100 50
0 100 a
c
d b
Recurrence or PD
PD during metastatic
setting
MPS of tumour tissue
MPS of circulating biomarkers
MPS of tumour tissue
MPS of circulating biomarkers
MPS M1 & M2 Discordant
results
MPS of circulating biomarkers
MPS of circulating biomarkers M1
M2
Therapy X
MPS of single biopsy Sample bias
Resistant clones (selected o ver time) Sensitive dominant clone
Other clones, which also bear resistant molecular alterations ctDNA
Therapy X
Therapy X
Therapy X + Y PD during
metastatic setting
PD during metastatic
setting
50
0 100
50
0 100
REVIEWS
NATURE REVIEWS | CLINICAL ONCOLOGY VOLUME 10 | JULY 2013 | 385
a marker of a population enriched for CSCs.
117Likewise, NOTCH1, which is a breast cancer oncogene related to self-renewing of breast cancer initiating cells, is reported to be expressed in approximately 60% of CTCs.
118CTCs in the bloodstream are considered to be enriched in CSCs,
119and this could further drive tumour initiation and, therefore, metastasis. Although there are many questions yet to be answered in this field, the detec- tion and molecular characterization of circulating CSCs could potentially have an impact on our understanding of metastasis in breast cancer, mechanisms of resistance and how circulating biomarkers should be assessed. An alternative interpretation for the observations that CTCs have phenotypic characteristics consistent with those of CSCs is that CTCs might be the result of an epithelial- to-mesenchymal (EMT) transition, and that numerous
markers and transcription factors expressed in cells undergoing EMT are also expressed in cells with CSC properties.
120Notably, EMT has been reported in CTCs obtained from patients with breast cancer.
121A dynamic balance of CTCs to either epithelial or mesenchymal states has been reported, and a mesenchymal CTC state has been shown to be associated with disease progression and therapeutic failure.
121It should be noted that mesen- chymal CTCs expressed EMT regulators, including compo nents of the TGF-β signalling pathway. Further studies to define whether CTCs are enriched for CSCs or cells undergoing EMT are warranted.
Clinically useful tools
Despite the interest in the implementation of circulat- ing biomarkers for the assessment of breast cancers, the
Figure 2 | Hypothesis for intratumour heterogeneity, therapeutic resistance and the potential role of blood-born circulating biomarkers. The model illustrates breast cancers harbouring intratumour heterogeneity, and how circulating biomarkers—
CTCs and ctDNA—constitute valuable non-invasive tools to recapitulate intratumour genomic characteristics. Graphs on the right show frequency of genomic alteration over time (for example, ctDNA copies/ ml or DNA extracted from CTCs).
a | There is a lack of tumour tissue after adjuvant therapy or during metastatic PD. MPS of circulating biomarkers could reveal molecular targets and a therapy X might be offered. b | MPS of both archival tumour tissue and circulating biomarkers reveal genomic alterations during PD, and one genomic alteration dominates in blood. Therapy X might be offered and there is reduction of one alteration (effective therapeutic intervention) while the other rises, indicating therapeutic resistance.
c | MPS of two metastatic sites, or the primary tumour and a metastatic deposit during PD give discordant results.
d | Spatial genetic heterogeneity within the primary tumour and/ or a metastatic deposit means that not all clones are sampled with a single biopsy. In parts c and d: MPS of circulating biomarkers could assist in the timely finding of actionable genomic alterations and in the clinical decision-making process. Abbreviations: CTCs, circulating tumour cells; ctDNA, cell-free tumour DNA; M, metastatic deposit; MPS, massively parallel sequencing; PD, progressive disease.
50
0 100 50
0 100
a
c
d b
Recurrence or PD
PD during metastatic setting
MPS of tumour tissue MPS of circulating biomarkers
MPS of tumour tissue MPS of circulating biomarkers
MPS M1 & M2 Discordant
results
MPS of circulating biomarkers
MPS of circulating biomarkers
M1 M2
Therapy X
MPS of single biopsy Sample bias
Resistant clones (selected o ver time) Sensitive dominant clone
Other clones, which also bear resistant molecular alterations ctDNA
Therapy X
Therapy X
Therapy X + Y PD during
metastatic setting
PD during metastatic
setting
50
0 100
50
0 100
REVIEWS
© 2013 Macmillan Publishers Limited. All rights reserved
What to look for..?
• Acquired resistance to TKIs in NSCLC (p.T790M EGFR;
ALK translocation and point mutations)
• Acquired resistance to antiEGFR in colon cancer (RAS mutations)
• Acquired resistance to hormonal treatment in breast cancer (ER mutations)
• Acquired resistance to hormonal treatment in CRPC
(AR splice variants)
AR-V7 and taxanes in mCRPC
1/19/2016
Antonarakis et al. JAMA Oncol 2015;1(5):582-91
33“From laboratory to clinic..”
APPROPRIATENESS
“From laboratory to clinic..”
THRESHOLD VALUE
APPROPRIATENESS
35
“From laboratory to clinic..”
THRESHOLD VALUE
CLINICAL RELEVANCE
APPROPRIATENESS
“From laboratory to clinic..”
THRESHOLD VALUE
CLINICAL RELEVANCE
GIVE A RESULT WITHOUT CLINICAL INFO
APPROPRIATENESS
37
“From laboratory to clinic..”
THRESHOLD VALUE
CLINICAL RELEVANCE
GIVE A RESULT WITHOUT CLINICAL INFO
VARIABLES FOR cftDNA
RELEASE
APPROPRIATENESS
“From laboratory to clinic..”
THRESHOLD VALUE
CLINICAL RELEVANCE
GIVE A RESULT WITHOUT CLINICAL INFO
VARIABLES FOR cftDNA
RELEASE
TUMOR BURDEN
APPROPRIATENESS
39
“From laboratory to clinic..”
THRESHOLD VALUE
CLINICAL RELEVANCE
GIVE A RESULT WITHOUT CLINICAL INFO
VARIABLES FOR cftDNA
RELEASE
TUMOR BURDEN
MTS SITES
APPROPRIATENESS
“From laboratory to clinic..”
THRESHOLD VALUE
CLINICAL RELEVANCE
GIVE A RESULT WITHOUT CLINICAL INFO
VARIABLES FOR cftDNA
RELEASE
TUMOR BURDEN
MTS SITES CT
APPROPRIATENESS
41
“From laboratory to clinic..”
THRESHOLD VALUE
CLINICAL RELEVANCE
GIVE A RESULT WITHOUT CLINICAL INFO
MOLECULAR MONITORING OPTIMAL TIMING VARIABLES FOR
cftDNA RELEASE
TUMOR BURDEN
MTS SITES CT
APPROPRIATENESS
“From laboratory to clinic..”
THRESHOLD VALUE
CLINICAL RELEVANCE
GIVE A RESULT WITHOUT CLINICAL INFO
SEVERAL
MECHANISMS OF RESISTANCE VARIABLES FOR
cftDNA RELEASE
TUMOR BURDEN
MTS SITES
CT MOLECULAR
MONITORING OPTIMAL TIMING
APPROPRIATENESS
43
“From laboratory to clinic..”
THRESHOLD VALUE
CLINICAL RELEVANCE
GIVE A RESULT WITHOUT CLINICAL INFO
SEVERAL
MECHANISMS OF RESISTANCE VARIABLES FOR
cftDNA RELEASE
TUMOR BURDEN
MTS SITES
CT MOLECULAR
MONITORING OPTIMAL TIMING
APPROPRIATENESS
“From laboratory to clinic..”
THRESHOLD VALUE
CLINICAL RELEVANCE
GIVE A RESULT WITHOUT CLINICAL INFO
SEVERAL
MECHANISMS OF RESISTANCE VARIABLES FOR
cftDNA RELEASE
TUMOR BURDEN
MTS SITES
CT MOLECULAR
MONITORING OPTIMAL TIMING
APPROPRIATENESS
45
“From laboratory to clinic..”
THRESHOLD VALUE
CLINICAL RELEVANCE
GIVE A RESULT WITHOUT CLINICAL INFO
SEVERAL
MECHANISMS OF RESISTANCE VARIABLES FOR
cftDNA RELEASE
TUMOR BURDEN
MTS SITES
CT MOLECULAR
MONITORING OPTIMAL TIMING
COSTS
APPROPRIATENESS
Lab’s issues
PRE-ANALYTICAL PHASE
FALSE NEG/POS RESULTS
CLINICAL REPORTS
47